The use of drugs which selectively protect normal tissues to a greater extent than tumors from the damaging effects of ionizing radiation is one means of increasing therapeutic gain in radiotherapy. Although a number of radioprotective compounds have been identified, the process of testing preferential response in animal-tumor models is longterm and limits rapid progress toward clinical trials. An in vivo assay based on quantitating radiation damage by observing micronucleus formation in both normal and tumor cells shows potential as a screening test for agents which may modify radiation response. We propose to develop the micronucleus assay and compare it to a number of established end points such as animal survival, tumor regrowth, and cell survival in healthy and tumor bearing mice. The test will be used to predict optimum dosage schedules and timing between drug administration and radiation treatment. Several known radioprotectors, including WR-2721 and WR-3689, will be used to evaluate the micronucleus assay. The investigation will emphasize experiments with diethyldithiocarbamate (DDC). DDC is a sulphydryl metal chelator that has been shown to protect animals from the lethal effects of radiation. Since DDC has been used clinically in humans for many years at doses that are known to confer radioprotection in animals, the potential exists for combined DDC-radiotherapy in man. The proposed research project is designed to answer a number of questions concerning the action of DDC in order to dtermine the feasibility of introducing DDC as radiation modifier in clinical radiotherapy. Whether or not DDC selectively modifies the radiation response of normal cells in comparison to tumor cells will be determined by using the RIF-1 animal tumor model with micronuclei frequency, LD50/30, tumor regrowth, and cell survival as end points. In addition, the relationship between tissue oxygenation and radioprotection by DDC and its metabolites will be examined. Reduction of cellular glutathione by DDC will be studied as a possible mechanism of action by analyzing in vitro survival curves from normal and glutathione deficient human fibroblasts.